tbuckley/cabot-search huggingface dataset:
Abstract PR010: First-in-class TRPV6 inhibitors for the treatment of prostate cancer
Authors: Kimberley Beaumont, Rebecca Pouwer, Raphael Rahmani, Matthew McLachlan, Claire Levrier, Rebecca Farrow, Mei Yeh, Therese Johnson, Malika Kumarasiri, Hasanthi Wijesekera, Grant Stuchbury, Terrie-Anne Cock, Andrew Harvey, Gregory Monteith, Brian Dymock
Journal: Cancer Research (2023)

Abstract TRPV6, a calcium channel, is an oncochannel that is overexpressed in epithelial cancers including prostate cancer. We have developed a novel series of first-in-class small molecule TRPV6 inhibitors for the treatment of advanced prostate cancer. Our preclinical candidate QED-203 has been shown to inhibit calcium influx at low nM potency in TRPV6 cellular assays (FLIPR, electrophysiology), and has low nM potency in a TRPV6-driven NFAT assay (NFAT luciferase reporter). Inhibition of TRPV6 with our TRPV6 inhibitors or by siRNA knockdown causes changes in genes related to NFAT and WNT signalling, ER stress and the cell cycle (RNAseq and qPCR analysis), and causes cell cycle arrest, decreased proliferation and apoptosis in prostate cancer cells (demonstrated via imaging and FACS analysis). Importantly, QED-203 demonstrates potency in enzalutamide resistant cell lines (in vitro proliferation inhibition) and has superior potency over enzalutamide and darolutamide [androgen receptor targeting agents (ARTA)] in prostate cancer cell lines with clinically relevant AR mutations or the ARV7 splice variant. The ARV7 variant in particular is represented in a significant portion of patients no longer responding to ARTA SoC interventions. QED-203 has high bioavailability with a pharmacokinetic profile amenable to once-a-day oral dosing. QED-203 is well tolerated in rodents and has similar in vivo efficacy (tumour growth and PSA inhibition) to enzalutamide in a castrated LNCaP mouse model of prostate cancer. We have also shown QED-203 target engagement in rodents by demonstrating a change in calcium levels in the urine, and have observed changes in genes consistent with a TRPV6-specific mode of action in xenograft tumours (demonstrated via qPCR). QED-203 targets a novel, non-hormonal mechanism in prostate cancer, and could be used to treat prostate cancer patients who have developed resistance to AR therapies, where there is a large unmet need. Citation Format: Kimberley Beaumont, Rebecca Pouwer, Raphael Rahmani, Matthew McLachlan, Claire Levrier, Rebecca Farrow, Mei Yeh, Therese Johnson, Malika Kumarasiri, Hasanthi Wijesekera, Grant Stuchbury, Terrie-Anne Cock, Andrew Harvey, Gregory Monteith, Brian Dymock. First-in-class TRPV6 inhibitors for the treatment of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR010.
Abstract PR009: Basal cell lineage plasticity in prostate homeostasis, repair and tumor initiation
Authors: Dong Gao
Journal: Cancer Research (2023)

Abstract Androgen deprivation is the paradigm of prostate cancer treatment. It is often linked to the loss of luminal cells, but the basal cell fates under androgen deprivation, prostatitis and cancer initiation remain unclear. Using a genetic proliferation tracer (ProTracer) system, we found that adult prostate basal cells also had extensive cell loss and proliferation during androgen-mediated prostate regression and regeneration. A rare basal population that expresses luminal cell genes (termed Basal-B) and a large basal population (termed Basal-A) were identified in the mouse prostate by single-cell RNA sequencing. Basal-B cells exhibited greater capacity for organoid formation and luminal cell differentiation in vitro. Basal-A and Basal-B cells were specifically tracked at the same time in vivo using a genetic lineage-tracing system that uses dual recombinases (Cre and Dre). Fate-mapping showed that prostate basal regeneration is not driven by rare Basal-B cells. Clonal analysis showed that Basal-B cells had the better tendency to generate luminal cells under bacteria-induced prostatitis. Moreover, oncogenic transformation of basal cells promoted the Basal-B cell marker gene expression in vivo. This study provides genetic evidence of a bona fide of basal cell lineage plasticity under androgen deprivation, prostatitis and oncogenic transformation contexts. Citation Format: Dong Gao. Basal cell lineage plasticity in prostate homeostasis, repair and tumor initiation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR009.
Studies on the Exchange of Fluids Between Host and Tumor. I. A Method for Growing “Tissue-Isolated” Tumors in Laboratory Animals&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Pietro M. Gullino, Flora H. Grantham
Journal: JNCI Journal of the National Cancer Institute (1961)

A technique is described which provides the investigator with a growing tumor enveloped in paraffin and thus isolated from the surrounding tissues but connected with the host by a single artery and vein from which blood can be withdrawn. The procedure can be applied to all tumors normally grown in a solid form in rats, hamsters, and mice. Two transplants of the same tumor, one grown isolated in the paraffin envelope and the other grown subcutaneously, showed the same correlation between wet weight, dry weight, and total nitrogen, as well as the same level of anaerobic glycolysis. Animals bearing the “isolated” transplants behaved in the same manner as those bearing subcutaneous tumors in regard to body weight, food consumption, and water intake; liver catalase was also equally depressed.
Proteus mirabilis – analysis of a concealed source of carbapenemases and development of a diagnostic algorithm for detection
Authors: Axel Hamprecht, Janko Sattler, Janina Noster, Yvonne Stelzer, Frieder Fuchs, Vivien Dorth, Sören G. Gatermann, Stephan Göttig
Journal: Clinical Microbiology and Infection (2023)

To analyse carbapenemases in Proteus mirabilis and assess the performance of carbapenemase detection assays.Eighty-one clinical P. mirabilis isolates with high-level resistance at least to ampicillin (>32 mg/L) or previous detection of carbapenemases were selected and investigated by three susceptibility testing methods (microdilution, automated susceptibility testing, and disk diffusion), six phenotypic carbapenemase assays (CARBA NP, modified carbapenemase inactivation method [CIM], modified zinc-supplemented CIM, simplified CIM, faropenem, and carbapenem-containing agar), two immunochromatographic assays, and whole-genome sequencing.Carbapenemases were detected in 43 of 81 isolates (OXA-48-like [n = 13]; OXA-23 [n = 12]; OXA-58 [n = 12]; New Delhi metallo-β-lactamase (NDM) [n = 2]; Verona integron-encoded metallo-β-lactamase (VIM) [n = 2]; Imipenemase (IMP) [n = 1]; Klebsiella pneumoniae carbapenemase (KPC) [n = 1]). Carbapenemase-producing Proteus were frequently susceptible to ertapenem (26/43; 60%), meropenem (28/43; 65%), ceftazidime (33/43; 77%), and some even to piperacillin-tazobactam (9/43; 21%). Sensitivity/specificity of phenotypic tests were 30% (CI: 17-46%)/89% (CI: 75-97%) for CARBA NP, 74% (CI: 60-85%)/82% (CI: 67-91%) for faropenem, 91% (CI: 78-97%)/82% (CI: 66-92%) for simplified CIM, and 93% (CI: 81-99%)/100% (CI: 91-100%) for modified zinc-supplemented CIM. An algorithm for improved detection was developed, which demonstrated sensitivity/specificity of 100% (CI: 92-100%)/100% (CI: 91-100%) on the 81 isolates, and 100% (CI: 29-100%)/100% (CI: 96-100%) in a prospective analysis of additional 91 isolates. Interestingly, several OXA-23-producing isolates belonged to the same clonal lineage reported previously from France.Current susceptibility testing methods and phenotypic tests frequently fail to detect carbapenemases in P. mirabilis, which could result in inadequate antibiotic treatment. In addition, the non-inclusion of blaOXA-23/OXA-58 in many molecular carbapenemase assays further impedes their detection. Therefore, the prevalence of carbapenemases in P. mirabilis is likely underestimated. With the herein proposed algorithm, carbapenemase-producing Proteus can be easily identified.
Occipital involvement in classic frontal fibrosing alopecia: Clinical and trichoscopic cross-sectional study in 17 patients
Authors: Raquel Pérez Mesonero, Elena Lucía Pinto Pulido, Alba Gómez Zubiaur, Dolores Vélez Velázquez, David Vega Díez, Ana Rodríguez-Villa Lario, Marta González-Cañete, Elena García Verdú, Pablo Vergara Pelayo, Lidia Trasobares Marugán
Journal: Journal of the American Academy of Dermatology (2023)
Abstract B063: Interplay between PARP and the RB/E2F axis in prostate cancer
Authors: Latese Evans, Moriah Cunningham, Jasibel Vasquez Gonzalez, Matthew Schiewer
Journal: Cancer Research (2023)

Abstract Retinoblastoma (RB) protein is a tumor suppressor that represses the transcriptional activity of E2Fs by forming an RB-E2F repressor complex. The phosphorylation of RB by CDK4/6 results in dissociation of the complex and subsequent E2F transcriptional activity, leading to cell cycle progression. RB loss occurs in 10-15% of castration-resistant prostate cancer (CRPC) which is associated tumor aggressiveness and poor clinical outcomes. RB loss is also associated differential treatment response to an array of treatment modalities, including hormone therapy and DNA damage inducing chemotherapy. RB depletion leads to enhanced expression of DNA repair proteins due to increased transcriptional activity of E2F1. PARP-1 is an enzyme that plays a role in multiple nuclear processes including DNA repair, transcriptional regulation, and chromatin dynamics. Increased PARP-1 activity is associated with and correlates to poor clinical outcomes in CRPC. E2F1 transcriptional activity is supported by PARP enzymatic activity, but the consequences of the functional interaction between the RB/E2F axis and PARP remains an open line of inquiry, which may yield novel treatment strategies and/or biomarkers of response. Isogenic models of RB1 knockdown were used to evaluate the impact of RB loss on PARP enzymatic activity. PARP-1 protein increases upon RB1 depletion with a concomitant increase in PARP activity. Growth curve assays were conducted to examine the biological response to PARP inhibition in the isogenic models. Results suggest a differential response between control and RB1 depleted cells when treated with Olaparib. RB1depleted cells also exhibit differential PARP activity in response to treatment with the IC50 dose of Olaparib. Future studies have been designed to evaluate the impact of RB alteration and manipulation of PARP activity on biological and molecular processes that are governed by RB/E2F and PARP. Citation Format: Latese Evans, Moriah Cunningham, Jasibel Vasquez Gonzalez, Matthew Schiewer. Interplay between PARP and the RB/E2F axis in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B063.
Abstract B002: Lactate metabolism regulates chromatin accessibility and prostate luminal differentiation
Authors: Andrew S. Goldstein, Jenna M. Giafaglione, Preston D. Crowell
Journal: Cancer Research (2023)

Abstract Lineage transitions are a central feature of prostate development, tumorigenesis and treatment resistance. While epigenetic changes drive prostate lineage transitions, whether upstream metabolic signaling modulates prostate lineage identity remains unclear. Investigations into prostate metabolism are focused primarily on targeting energy metabolism without considering how altering metabolism may influence epigenetic state or cellular differentiation. To understand the relationship between metabolism and prostate lineage identity, we developed an approach to perform metabolic profiling and nutrient tracing on primary prostate epithelial cells and demonstrated that basal and luminal cells exhibit distinct metabolic features. Furthermore, we show that basal to luminal differentiation in vivo and in three-dimensional ex vivo culture is accompanied by metabolic changes consistent with increased glucose oxidation. Using genetic and pharmacological approaches, we identify the mitochondrial pyruvate carrier (MPC) as a regulator of prostate luminal identity in benign and prostate cancer cells. Low MPC expression is inversely correlated with luminal differentiation and associated with poor response to androgen receptor inhibition in clinical prostate cancer. Mechanistically, our results suggest that MPC inhibition likely impairs luminal differentiation through accumulation of intracellular lactate. Increasing intracellular lactate levels is sufficient to alter chromatin accessibility at lineage-specific genes and impair luminal differentiation in prostate epithelial cells. These findings indicate that upstream metabolism is a regulator of chromatin accessibility and prostate lineage differentiation, suggesting that alterations in tumor metabolism may contribute to lineage plasticity and resistance to androgen receptor blockade in prostate cancer. Citation Format: Andrew S. Goldstein, Jenna M. Giafaglione, Preston D. Crowell. Lactate metabolism regulates chromatin accessibility and prostate luminal differentiation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B002.
Abstract A013: Minor intron splicing is critical for survival of lethal prostate cancer
Authors: Anke Augspach, Mark Andrew Rubin, Rahul Kanadia
Journal: Cancer Research (2023)

Abstract The role of major intron splicing in PCa is well established and highly investigated. However, the equally important and impactful minor spliceosome (MiS) and minor intron splicing have remained underexplored in PCa. Here for the first time, we show that minor intron containing genes (MIGs) are enriched as direct interactors of PCa-causing genes and that their expression levels correspond to different stages of PCa progression. Accordingly, we show that U6atac expression and MiS activity reinforces cell growth and correlates with PCa progression. Consequently, highly proliferative PCa cells are strongly susceptible to siU6atac-mediated MiS inhibition. In this sense, siU6atac is significantly more efficient in lowering the tumor burden of castration resistant prostate cancer (CRPC) cells and organoids than the current state-of-the-art combination therapy. Mechanistically, we show that inhibition of the MiS through siU6atac causes minor and major intron mis-splicing and aberrant expression of MIG and non-MIG transcripts and encoded proteins, which enriches for MAPK activity, DNA repair, and cell cycle. Single cell-RNAseq confirms cell cycle defects and lineage dependency on the MiS from primary to CRPC and neuroendocrine PCa. Finally, our data provides strong evidence that Androgen receptor signaling functions as a regulator of MiS activity throughout PCa disease progression to CRPC while p38MAPK influences MiS activity in neuroendocrine PCa. Furthermore, we discovered that MiS inhibition in neuroendocrine PCa shifts alternative splicing in favor of canonical REST1 isoform thereby blocking lineage plasticity and progression to lethal therapy resistant PCa. This finding positions the MiS as yet another disruptor of a crucial molecular pathway underpinning the emergence of CRPC and neuroendocrine PCa. Based on these findings we posit that the MiS may be a common denominator of prominent PCa driver genes and a driving factor of advanced lethal PCa. We hypothesize that the MiS represents a point of vulnerability in therapy-resistant PCa. Citation Format: Anke Augspach, Mark Andrew Rubin, Rahul Kanadia. Minor intron splicing is critical for survival of lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A013.
Abstract B069: SPOP loss places the prostate luminal epithelial cells at a selective disadvantage
Authors: Kinza Rizwan, Darlene Skapura, Cammy Mason, Cristian Coarfa, Nicholas Mitsiades, Damian Young, Salma Kaochar
Journal: Cancer Research (2023)

Abstract Background: Prostate cancer (PC) is the single most common and second-most lethal cancer in men, with over 268,000 estimated cases and over 34,500 estimated deaths in the US in 2022. The Speckle-Type POZ protein (SPOP) mutant subclass of PC accounts for 10% to 15% of all primary PC cases. SPOP is an adaptor for Cullin3/Ring (CUL3-RING)-type E3 ubiquitin ligase complexes and provides substrate specificity. The Cancer Genome Atlas (TCGA) studies show that SPOP is the most frequently mutated gene in primary prostate cancer (PC). Interestingly, PC-associated SPOP mutations are always missense and occur in a heterozygous fashion. The current gap in knowledge is the lack of understanding of the role of wildtype SPOP in PC. Methods: By utilizing prostate specific SPOP knockout (KO) mice, we recently reported increased levels of AR and MYC protein and increased cellular turnover (both proliferation and apoptosis) in the prostate luminal epithelium compared to wildtype prostates. We now characterized these mice for the expression of Cre protein and SPOP mRNA at different age using immunohistochemistry and RNA in situ hybridization. Furthermore, we performed RNA-sequencing analysis in the SPOP knockout mice and matched control littermates. Moreover, we performed RNA-seq in LNCaP, LNCaP-Abl, and RWPE1 cells following SPOP inhibition via siRNA targeting SPOP. Finally, we compared our SPOP inhibition signature from in vitro cell lines and prostate specific SPOP knockout murine model to gain insights about the role of wildtype SPOP protein in the prostate epithelium. Result: Using our Spopfl/fl;PBCre+ model, we observed SPOP floxed cells are rapidly lost and the murine prostate epithelium was repopulated with SPOP wildtype carrying cells. Similarly, knockdown (KD) of SPOP through siRNA treatment in a panel of PC cell lines resulted in a significant reduction in cell viability. These observations suggest that SPOP is important for the normal prostate cell viability. Further transcriptomic profiling of SPOP KO (from transgenic murine model) as well as siSPOP treated in vitro prostate cell lines revealed a significant reduction in the transcriptional activity of the AR. Conclusion: Our data illustrate for the first time a critical role for SPOP in the growth and survival of the prostate epithelium and prostate cancer cell. Our findings further validates SPOP as a important therapeutic target for the treatment of prostate cancer. Citation Format: Kinza Rizwan, Darlene Skapura, Cammy Mason, Cristian Coarfa, Nicholas Mitsiades, Damian Young, Salma Kaochar. SPOP loss places the prostate luminal epithelial cells at a selective disadvantage [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B069.
Abstract B037: Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases
Authors: Shang Su, Ke Liu, Jing Xing, Yawei Zhao, Ruihua Liu, Bin Chen, Xiaohong Li
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) patients’ 5-year survival is only ~30% when metastases develop. Most PCa metastases happen in bone. We seek to identify gene signatures unique for bone-metastatic PCa cells and explore potential drug candidates to specifically target PCa bone metastases (bone met). Using public RNA-Seq datasets, we defined differentially expressed genes (DE) intrinsic to PCa bone met by analyzing the DE between bone mets (MET500) and primary tumors (TCGA) and filtering out the genes shown as the DE between normal bone marrow and prostate (GTex). Similarly, we got DE intrinsic to liver met. These two intrinsic DE were further compared and functional annotation for bone met only DE was performed. We found that the bone met only up-regulated DE were significantly enriched for mitochondrial OXPHOS and electron transport chain (ETC). In contrast, no mitochondria-related terms were enriched in PCa liver met, PCa lymph node met or breast cancer bone met, suggesting unique elevated mitochondrial activities in PCa bone met. We further performed RNA-Seq analyses and determined the DE unique in intratibial xenografts (mimicking bone mets), compared to C4-2B PCa primary tumors, i.e., orthotopic or subcutaneous xenografts. OXPHOS was also positively enriched in the intratibial DE, suggesting that pre-clinical animal models recapitulate functional signatures of PCa patients and can be used for drug testing. Therefore, we hypothesized that inhibiting mitochondrial OXPHOS or ETC complex blocks PCa bone metastases. Excitingly, we found that mitochondrial ETC complex I inhibitor, IACS-010759, showed high potency and specificity in suppressing PCa cell growth without affecting osteoblasts in vitro, and significantly inhibited metastatic development of PCa cells in vivo. In summary, elevated mitochondrial activity appears to be a unique signature and phenotype for PCa bone met and mitochondria-interrupting drugs selectively suppress the growth of PCa cells without affecting normal cells in the bone microenvironment such as osteoblasts. Blocking mitochondria hyperactivation is a potential approach against PCa bone met. Citation Format: Shang Su, Ke Liu, Jing Xing, Yawei Zhao, Ruihua Liu, Bin Chen, Xiaohong Li. Elevated mitochondrial activity is a targetable signature of prostate cancer bone metastases [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B037.